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International Journal for Pharmaceutical
Research Scholars (IJPRS) V-3, I-2, 2014 ISSN No: 2277 - 7873
REVIEW ARTICLE
© Copyright reserved by IJPRS Impact Factor = 1.0285 814
Floating Drug Delivery System - A Review
Meraj Sualtana Syed*1, Lalitha ChVS2, Anusha Reddy C3, Surendra P4, Kalpana5 1Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopeta -522601.
2A.S.N.College of Pharmacy, Tenali - 522201. 3Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopeta -522601. 4Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopeta -522601.
5Victoria College of Pharmacy, Guntur - 522005. Manuscript No: IJPRS/V3/I2/00315, Received On: 19/06/2014, Accepted On: 29/06/2014
ABSTRACT
In recent years, scientific and technological advancements have been made in the research and
development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such
as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several
approaches are currently utilized in the prolongation of the GRT, including floating drug delivery
systems (FDDS), also known as Gastroretentive systems, hydrodynamically balanced systems (HBS),
swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density
systems, and other delayed gastric emptying devices can remain in the gastric region for several hours
and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves
bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH
environment. The purpose of writing this review is to focus on the principal mechanism of floating to
achieve gastric retention. This review involves classification, mechanism of floating, factors affecting
FDDS, in- vitro and in-vivo techniques and applications of these systems.
KEYWORDS
FDDS, Single and Multiple Units, Evaluation Tests and Applications
INTRODUCTION
The oral route is the most preferred route of
administration of drugs because of low cost of
therapy, ease of administration, patient
compliance and flexibility in formulation, etc.
During the past few decades, numerous oral
drug delivery systems have been developed to
act as drug reservoirs from which the active
substance can be released over a specific period
of time at a predetermined and controlled rate. It
is evident from the recent scientific and patent
literatures that an increased interest in novel oral
Controlled release dosage forms that designed to
be retained in the gastrointestinal tract (GIT) for
a prolonged and predictable period of time exist
today. Several approaches are currently utilized
in the prolongation of the gastric residence
times (GRT), including floating drug delivery
systems (FDDS).
Floating drug delivery systems (FDDS) are
those systems which have a bulk density less
than gastric fluids and because of this, these
systems remains buoyant (3-4 hours) for a
prolonged period of time in the stomach without
affecting the gastric emptying rate. The drug is
released slowly at the desired rate from the
system and after release of the drug; the residual
*Address for Correspondence:
Meraj sultana S.
Narasaraopeta Institute of Pharmaceutical Sciences,
Narasaraopeta -522601, Andhra Pradesh, India.
E-Mail Id: [email protected]
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system is emptied from the stomach. As a result
GRT is increased and fluctuations in plasma
drug concentration can be better controlled.
Gastroretentive systems can remain in the
gastric region for several hours and hence
significantly prolong the gastric residence time
of drugs. Prolonged gastric retention improves
bioavailability, reduces drug waste, and
improves solubility for drugs that are less
soluble in a high pH environment. It has
applications also for local drug delivery to the
stomach and proximal small intestines. Gastro
retention helps to provide better availability of
new products with new therapeutic possibilities
and substantial benefits for patients. The gastric
emptying of dosage forms is an extremely
variable process and ability to prolong and
control the emptying time is a valuable asset for
dosage forms that reside in the stomach for a
longer period of time than conventional dosage
forms.
A lot of scientific and technological
advancements have been made in the drug
delivery research in the recent years.
Physiological problems like short Gastric
Residence Time (GRT) and the unpredictable
Gastric Emptying Time (GET) were overcome
with the use of floating dosage forms which
provide opportunity for both local and systemic
drug action.
Gastrointestinal Tract Physiology
Figure 1: Structure of Stomach
Classification of Gastro Retentive Drug
Delivery System
Anatomically the stomach is divided into 3
regions: fundus, body, and antrum (pylorus).
The proximal part made of fundus and body acts
as a reservoir for undigested material, whereas
the antrum is the main site for mixing motions
and act as a pump for gastric emptying by
propelling actions. The proximal part made of
fundus and body acts as a reservoir for
undigested material, whereas the antrum is the
main site for mixing motions and act as a pump
for gastric emptying by propelling actions.
Table 1: PH and Transit Time values GIT
PH Values Transit Time
Fluids Solids
Stomach
Duodenum
Small Intestine
Rectum
1-3.5
5-7
6-7
7
50 Min
-
2 – 6 Hr
2 – 6 Hr
8 Hr
-
4 – 9 Hr
3 Hr – 3
Days
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Gastic Emptying
Gastric emptying occurs during fasting as well
as fed states1. The pattern of motility is however
distinct in the 2 states. During the fasting state
an inter digestive series of electrical events take
place, which cycle both through stomach and
intestine every 2 to 3 hours. This is called the
interdigestive myloelectric cycle or migrating
myloelectric cycle (MMC), which is further
divided into following 4 phases as described by
Wilson and Washington:
Phase I (basal phase) lasts from 40 to 60
minutes with rare contractions.
Phase II (preburst phase) lasts for 40 to 60
minutes with intermittent action potential and
contractions. As the phase progresses the
intensity and frequency also increases gradually.
Phase III (burst phase) lasts for 4 to 6 minutes.
It includes intense and regular contractions for
short period. It is due to this wave that all the
undigested material is swept out of the stomach
down to the small intestine. It is also known as
the housekeeper wave.
Phase IV lasts for 0 to 5 minutes and occurs
between phases III and I of 2 consecutive
cycles.
Figure 2: Phases of gastric emptying
After the ingestion of a mixed meal, the pattern
of contractions changes from fasted to that of
fed state. This is also known as digestive
motility pattern and comprises continuous
contractions as in phase II of fasted state. These
contractions result in reducing the size of food
particles (to less than 1 mm), which are
propelled toward the pylorus in a suspension
form. During the fed state onset of MMC is
delayed resulting in slowdown of gastric
emptying rate Scintigraphic studies determining
gastric emptying rates revealed that orally
administered controlled release dosage forms
are subjected to basically 2 complications, that
of short gastric residence time and unpredictable
gastric emptying rate.
Need for Gastro Retention
Drugs are absorbed from the proximal part
of the gastrointestinal tract (GIT).
Drugs are less soluble or are degraded by the
alkaline pH they encounter at the lower part
of GIT.
Drugs are absorbed due to variable gastric
emptying time.
Local sustained drug delivery to stomach
and proximal Small intestine to treat certain
conditions.
Particularly useful for the treatment of
peptic ulcers caused by H. Pylori Infections.
Formulation Considerations for GRDDS
It must be effective retention in the stomach to
suit for the clinical demand
It must have sufficient drug loading capacity
It must be control the drug release profile
It must have full degradation and evacuation
of the system once the drug release is over
It should not have effect on gastric motility
including emptying pattern
It should not have other local adverse
effects.
Drug Candidates Suitable For GRDDS
Drugs those are locally active in stomach.
Eg: Misoprostal, Antacids
Drugs with narrow absorption window in
GIT. Eg: Furosemide, Riboflavin, L-DOPA
Drugs those are unstable in intestinal or
colonic fluids. Eg: Captopril, Metronidazole
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Drugs that kill the microbial flora in
intestine. Eg: Antibiotics
Drugs that has low solubility at high PH. Eg:
Diazepam, Verapamil
Drug Candidates not Suitable for GRDDS
Drugs with very limited acid solubility. Eg:
Phenytoin
Drugs those are instable in gastric
environment
Drugs that are intended for release in lower
parts of GIT i.e. colon, rectum Eg:5-amino
salicylic acid, Corticosteroids
Requirements for Gastric Retention
From the discussion of the physiological factors
in the stomach it must be noted that to achieve
gastric retention, the dosage form must satisfy
certain requirements.
One of the key issues is that the dosage form
must be able to withstand the forces caused by
peristaltic waves in the stomach and the
constant contractions and grinding and churning
mechanisms2. To function as a gastric retention
device, it must be resist premature gastric
emptying. Furthermore, once its purpose has
been served, the device should be removed from
the stomach with ease.
Factors Affecting Floating Drug Delivery
System
The following factors affect the floating drug
delivery systems in GIT3.
Density
Density of the dosage form should be less than
the gastric contents (1.004gm/ml).
Size and Shape
Dosage form unit with a diameter of more than
7.5 mm are reported to have an increased GRT
competed to with those with a diameter of 9.9
mm. The dosage form with a shape tetrahedron
and ring shape devises with a flexural modulus
of 48 and 22.5 kilopond per square inch (KSI)
are reported to have better GIT for 90 to 100%
retention at 24 hours compared with other
shapes.
Fed or Unfed State
Under fasting conditions, the GI motility is
characterized by periods of strong motor activity
or the migrating myoelectric complexes (MMC)
that occurs every 1.5 to 2 hours. The MMC
sweeps undigested material from the stomach
and if the timing of administration of the
formulation coincides with that of the MMC, the
GRT of the unit can be expected to be very
short. However, in the fed state, MMC is
delayed and GRT is considerably longer.
Nature of the Meal
Feeding of indigestible polymers of fatty acid
salts can change the motility pattern of the
stomach to a fed state, thus decreasing the
gastric emptying rate and prolonging the drug
release.
Caloric Content
GRT can be increased between 4 to 10 hours
with a meal that is high in proteins and fats.
Frequency of Feed
The GRT can increase by over 400 minutes
when successive meals are given compared with
a single meal due to the low frequency of MMC.
Gender
Mean ambulatory GRT in meals (3.4±0.4 hours)
is less compared with their age and race-
matched female counterparts (4.6±1.2 hours),
regardless of the weight, height and body
surface.
Age
Elderly people, especially those over 70 years
have a significantly longer GRT.
Posture
GRT can vary between supine and upright
ambulatory states of the patients
Concomitant Drug Administration
Anticholinergic like atropine and propentheline
opiates like codeine and prokinetic agents like
metoclopramide and cisapride.
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Single or Multiple Unit Formulation
Multiple unit formulations show a more
predictable release profile and insignificant
impairing of performance due to failure of units,
allow co-administration of units with different
release profiles or containing incompatible
substances and permit a larger margin of safety
against dosage form failure compared with
single unit dosage forms.
Advantages of FDDS
The Floating systems are advantageous for
drugs meant for local action in the stomach.
E.g. antacids.
Acidic substances like aspirin cause
irritation on the stomach wall when come in
contact with it. Hence FDDS may be useful
for the administration of aspirin and other
similar drugs.
The Floating systems are advantageous for
drugs absorbed through the stomach. E.g.
Ferrous salts, antacids.
Administration of prolongs release floating
dosage forms, tablet or capsules, will result
in dissolution of the drug in the gastric fluid.
They dissolve in the gastric fluid would be
available for absorption in the small
intestine after emptying of the stomach
contents.
It is therefore expected that a drug will be
fully absorbed from floating dosage forms if
it remains in the solution form even at the
alkaline pH of the intestine.
Disadvantages of FDDS
Floating system is not feasible for those
drugs that have solubility or stability
problem in G.I. tract.
These systems require a high level of fluid
in the stomach for drug delivery to float and
work efficiently coat, water.
The drugs that are significantly absorbed
throughout gastrointestinal tract, which
undergo significant first pass metabolism,
are only desirable candidate.
Floating Drug Delivery System
The concept of FDDS was described in the
literature as early as 1962.Floating drug delivery
system is also called as hydro dynamically
balanced system (HBS). It has a bulk density
which is less than the gastric contents and hence
remains buoyant in the stomach for a prolonged
period of time without affecting the gastric
emptying rate for a prolonged period of time4.
While the system is floating on the gastric
contents the drug is released slowly at the
desired rate from the system. This results in an
increased GRT and a better control of
fluctuations in plasma drug concentration. The
device must have sufficient structure to form a
cohesive gel barrier, it must maintain an overall
specific gravity lower than that of gastric
contents (1.004-1.010) and it should dissolve
slowly enough to serve as a drug reservoir.
Many buoyant systems have been developed
based on granules, powders, capsules, tablets,
laminated films and hollow microspheres.
Table 2: Types of different buoyant forms
Dosage Forms Drugs
Tablets
Cholrpheniramine,
Theophylline, Furosemide,
Ciprofloxaci, Captopril,
Acetylsalicylic
acid, Amoxycillin trihydrate,
Verapamil HCI, Isosorbide
dinitrate, Isosorbide
mononitrate,
Acetaminophen, Ampicillin,
Cinnarazine, Dilitiazem,
Florouracil, Prednisolone,
Capsules
Nicardipine,
Chlordiazepoxide HCI,
Furosemide, Misoprostal,
Diazepam, Propranal
Urodeoxycholic acid.
Microsperes
Aspirin, Griseofulvin, and p-
nitroanilline, Ketoprofen,
Iboprufen, Terfenadine
Granules Indomethacin, Diclofenac
sodium, Prednisolone
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Mechanism of Floating Systems
Various attempts have been made to retain the
dosage form in the stomach as a way of
increasing the retention time. These attempts
include introducing floating dosage forms (gas-
generating systems and swelling or expanding
systems), mucoadhesive systems, high-density
systems, modified shape systems, gastric-
emptying delaying devices and co-
administration of gastric-emptying delaying
drugs. Among these, the floating dosage forms
have been most commonly used. Floating drug
delivery systems (FDDS) have a bulk density
less than gastric fluids and so remain buoyant in
the stomach without affecting the gastric
emptying rate for a prolonged period of time5.
While the system is floating on the gastric
contents (given in the Figure 3, the drug is
released slowly at the desired rate from the
system. After release of drug, the residual
system is emptied from the stomach.
This results in an increased GRT and a better
control of the fluctuations in plasma drug
concentration. However, besides a minimal
gastric content needed to allow the proper
achievement of the buoyancy retention
principle, a minimal level of floating force (F) is
also required to keep the dosage form reliably
buoyant on the surface of the meal. To measure
the floating force kinetics, a novel apparatus for
determination of resultant weight has been
reported in the literature. The apparatus operates
by measuring continuously the force equivalent
to F (as a function of time) that is required to
maintain the submerged object. The object
floats better if F is on the higher positive side
(Figure 3). This apparatus helps in optimizing
FDDS with respect to stability and durability of
floating forces produced in order to prevent the
drawbacks of unforeseeable intragastric
buoyancy capability variations.
F = F buoyancy - F gravity
= (Df - Ds) gv…….. (1)
Where, F= total vertical force, Df = fluid
density,
Ds = object density, v = volume and g =
acceleration due to gravity.
Figure 3: Mechanism of Floating Systems, GF=
Gastric fluid
Types of Floating Drug Delivery Systems
Based on the mechanism of buoyancy and two
distinctly different technologies have
been utilized in the development of FDDS.
1) Non- Effervescent FDDS
2) Effervescent FDDS
Non-Effervescent FDDS
The Non-effervescent FDDS is based on
mechanism of swelling of polymer or
bioadhesion to mucosal layer in GI tract6. The
most commonly used excipients in non-
effervescent FDDS are gel forming or highly
swellable cellulose type hydrocolloids,
hydrophilic gums, polysaccharides and matrix
forming materials such as polycarbonate,
polyacrylate, polymethacrylate, polystyrene as
well as bioadhesive polymers such as Chitosan
and carbopol.
Figure 4: HBS Capsule
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The various types of this system are as:
A. Single Layer Floating Tablets
They are formulated by intimate mixing of drug
with a gel-forming hydrocolloid, which swells
in contact with gastric fluid and maintains bulk
density of less than unity7. They are formulated
by intimate mixing of drug with low-density
enteric materials such as CAP, HPMC.
B. Bi-layer Floating Tablets
A bi-layer tablet contain two layer one
immediate release layer which releases initial
dose from system while the another sustained
release layer absorbs gastric fluid, forming an
impermeable colloidal gel barrier on its surface,
and maintain a bulk density of less than unity
and thereby it remains buoyant in the stomach.
Figure 5: Bilayer Floating Tablet
C. Alginate Beads
Multi-unit floating dosage forms were
developed from freeze-dried calcium alginate.
Spherical beads of approximately 2.5 mm
diameter can be prepared by dropping sodium
alginate solution into aqueous solution of
calcium chloride, causing precipitation of
calcium alginate leading to formation of porous
system, which can maintain a floating force for
over 12 hours8. When compared with solid
beads, which gave a short residence time of 1
hour, and these floating beads gave a prolonged
residence time of more than 5.5 hours.
D. Hollow Microspheres
Hollow microspheres (microballoons), loaded
with drug in their outer polymer shells are
prepared by a novel emulsion-solvent diffusion
method. The ethanol: dichloromethane solution
of the drug and an enteric acrylic polymer is
poured into an agitated aqueous solution of
PVA that is thermally controlled at 400C. The
gas phase generated in dispersed polymer
droplet by evaporation of dichloromethane
forms an internal cavity in microsphere of
polymer with drug. The microballoons float
continuously over the surface of acidic
dissolution media containing surfactant for more
than 12 hours in vitro.
Figure 6: Hollow Microspheres
Effervescent System
Effervescent systems include use of gas
generating agents, carbonates (e.g Sodium
bicarbonate) and other organic acid (e.g. Citric
acid and tartaric acid) present in the formulation
to produce carbon dioxide (CO2) gas, thus
reducing the density of the system and making it
float on the gastric fluid9. An alternative is the
incorporation of matrix containing portion of
liquid, which produce gas that evaporates at
body temperature. These effervescent systems
further classified into two types.
A. Gas generating systems
B. Volatile liquid/vacuum containing systems
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Gas Generating Systems
Tablets
Floating bilayer tablets with controlled release
for furosemide were developed by. The low
solubility of the drug could be enhanced by
using the kneading method, preparing a solid
dispersion with ß cyclodextrin mixed in a 1:1
ratio. One layer contained the polymers HPMC
K4M, HPMC K100M and CMC (for the control
of the drug delivery) and the drug. The second
layer contained the effervescent mixture of
sodium bicarbonate and citric acid.
The in-vitro floating studies revealed that the
lesser the compression force the shorter is the
time of onset of floating, i.e., when the tablets
were compressed at 15 MPa, these could begin
to float at 20 minutes whereas at a force of 32
MPa the time was prolonged to 45 minutes.
Radiographic studies on 6 healthy male
volunteers revealed that floating tablets were
retained in stomach for 6 hours and further
blood analysis studies showed that
bioavailability of these tablets was 1.8 times that
of the conventional tablets.
On measuring the volume of urine the peak
diuretic effect seen in the conventional tablets
was decreased and prolonged in the case of
floating dosage form.
Floating Capsules
Floating capsules are prepared by filling
with a mixture of sodium alginate and
sodium bicarbonate. The systems were shown to
float during in vitro tests as a result of the
generation of CO2 that was trapped in the
hydrating gel network on exposure to an acidic
environment.
Multiple Unit Type Floating Pills
The system consists of sustained release pills as
‘seeds’ surrounded by double layers. The inner
layer consists of effervescent agents while the
outer layer is of swell able membrane layer.
When the system is immersed in dissolution
medium at body temp, it sinks at once and then
forms swollen pills like balloons, which float as
they have lower density. This lower density is
due to generation and entrapment of CO2 within
the system.
Figure 7: Multiple Unit Floating Pills
A. Different layers in floating pills
i. Semi-permeable membrane
ii. Effervescent layer
iii. Core pill layer
B. Mechanism of floatation via CO2 generation.
Floating System with Ion-Exchange Resins
A floating system using ion exchange resin that
was loaded with bicarbonate by mixing the
beads with 1M sodium bicarbonate solution.
The loaded beads were then surrounded by a
semipermeable membrane to avoid sudden loss
of CO2. Upon coming in contact with gastric
contents an exchange of chloride and
bicarbonate ions took place that resulted in CO2
generation thereby carrying beads toward the
top of gastric contents and producing a floating
layer of resin beads. The in-vivo behavior of the
coated and uncoated beads was monitored using
a single channel analyzing study in 12 healthy
human volunteers by gamma radio scintigraphy.
Studies showed that the gastric residence time
was prolonged considerably (24 hours)
compared with uncoated beads (1 to 3 hours).
Figure 8: Floating System with Ion Exchange
Resin
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Volatile Liquid / Vacuum Containing
Systems
Intra-gastric Floating Gastrointestinal Drug
Delivery System
These systems can be made to float in the
stomach because of floatation chamber, which
may be a vacuum or filled with air or a harmless
gas, while drug reservoir is encapsulated inside
a micro-porous compartment.
Figure 9: Intragastric Floating GDDS
Inflatable gastrointestinal delivery systems
In these systems an inflatable chamber is
incorporated, which contains liquid ether that
gasifies at body temperature to cause the
chamber to inflate in the stomach. These
systems are fabricated by loading the inflatable
chamber with a drug reservoir, which can
be a drug impregnated polymeric matrix,
encapsulated in a gelatin capsule. After oral
administration, the capsule dissolves to release
the drug reservoir together with the inflatable
chamber. The inflatable chamber automatically
inflates and retains the drug reservoir
compartment in the stomach. The drug
continuously released from the reservoir into the
gastric fluid.
Figure 10: Inflatable GDDS
Intragastric Osmotically Controlled Drug
Delivery System
It is comprised of an osmotic pressure
controlled drug delivery device and an inflatable
floating support in a biodegradable capsule. In
the stomach, the capsule quickly disintegrates to
release the intragastric osmotically controlled
drug delivery device. The inflatable support
inside forms a deformable hollow polymeric bag
that contains a liquid that gasifies at body
temperature to inflate the bag. The osmotic
pressure controlled drug delivery device
consists of two components; drug reservoir
compartment and an osmotically active
compartment.
The drug reservoir compartment is enclosed by
a pressure responsive collapsible bag, which is
impermeable to vapour and liquid and has a
drug delivery orifice. The osmotically active
compartment contains an osmotically active salt
and is enclosed within a semipermeable
housing. In the stomach, the water in the GI
fluid is continuously absorbed through the semi-
permeable membrane into osmotically active
compartment to dissolve the osmotically active
salt.
The osmotic pressure thus created acts on the
collapsible bag and in turn forces the drug
reservoir compartment to reduce its volume and
activate drug release through the delivery
orifice. The floating support is also made to
contain a bioerodible plug that erodes after a
predetermined time to deflate the support. The
deflated drug delivery system is then emptied
from the stomach.
Figure 11: Intragastric Osmotically Controlled
Drug Delivery System
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Other Types of Gastroretentive Systems
Bioadhesive Drug Delivery System
The term bioadhesion is defined as adhesion to
biological surface i.e. Mucus and/or mucosal
surface. In instances when the polymeric
system interacts with mucus layer only, it is
referred as mucoadhesion10. In order to
develop an ideal oral bioadhesive system, it is
important to have a thorough understanding of
mucosa, bioadhesive polymers and mucin-
polymer interactions in the physiological
environment. Intestinal mucosa is composed of
high molecular weight glycoproteins hydrated
and covering the mucosa with a continuous
adherent blanket. Mucin glycoproteins are rich
with fucose and sialic acid groups at the
terminal ends which provide a net negative
charge in the acidic environment. The thickness
of the mucin gel layer varies in different regions
of the GIT with thickness ranging between 50-
500 µm in stomach to 15-150µm in the colon.
Cohesion of the mucin gel is dependent upon
the glycoprotein concentration. The mucus
layer is created biologically to play a
number of important functions of protecting
the underlying tissues from various
diffusing/corrosive elements such as enzymes,
acid and other toxic molecules. Also being a
visco-elastic gel, it helps in the passage of food
over the epithelium, thereby minimizing
potential erosive damages. The mucus layer, in
addition to providing protection, provides a
barrier to drug absorption. Various investigators
have proposed different mucin-polymer
interactions, such as Wetting and swelling of the
polymer to permit intimate contact with the
biological tissue. Interpenetration of
bioadhesive polymer chains and entanglement
of polymer and mucin chains. Formation of
weak chemical bonds sufficient polymer
mobility to allow spreading Water transport
followed by mucosal dehydration.
As the mucus layer comes into contact with
bioadhesive coated system, various non-
specific (Vander Waals, hydrogen bonding
and/or hydrophobic interactions) or specific
interactions occur between the complimentary
structures. However, these interactions last only
until the turnover process of mucin and, in order
for a bioadhesive system to be successful; it
should release its drug contents during this
limited adhesion time.
Raft-Forming Systems
Here, a gel-forming solution (e.g. sodium
alginate solution containing carbonates or
bicarbonates) swells and forms a viscous
cohesive gel containing entrapped CO2
bubbles on contact with gastric fluid.
Formulations also typically contain antacids
such as aluminium hydroxide or calcium
carbonate to reduce gastric acidity. Because
raft-forming systems produce a layer on the top
of gastric fluids, they are often used for gastro
esophageal reflux treatment as with liquid
gaviscon.
High Density Systems
Gastric contents have a density close to water
(1.004 g /cm3). When the patient is upright
small high-density pellets sink to the bottom of
the stomach where they become entrapped in
the folds of the antrum and withstand the
peristaltic waves of the stomach wall. A density
close to 2.5 g/cm seems necessary for
significant prolongation of gastric residence
time and barium sulphate, zinc oxide, iron
powder, titanium dioxide are used as excipients.
Low Density Systems
Gas-generating systems inevitably have a lag
time before floating on the stomach contents,
during which the dosage form may undergo
premature evacuation through the pyloric
sphincter. Low-density systems (<1 g/cm3)
with immediate buoyancy have therefore been
developed. They are made of low-density
materials, entrapping oil or air. Most are
multiple unit systems, and are also called
‘‘microballoons’’ because of the low-density
core. Generally, techniques used to prepare
hollow microspheres involve simple solvent
evaporation or solvent diffusion methods.
Polycarbonate, Eudragit S, cellulose acetate,
calcium alginate, agar and low methoxylated
pectin are commonly used as polymers11.
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Buoyancy and drug release are dependent on
quantity of polymer, the plasticizer–polymer
ratio and the solvent used.
Expandable Systems
A dosage form in the stomach will withstand
gastric transit if it is bigger than the pyloric
sphincter. However, the dosage form must be
small enough to be swallowed, and must not
cause gastric obstruction either singly or by
accumulation. Thus, three configurations are
required, a small configuration for oral intake,
an expanded gastroretentive form and a final
small form enabling evacuation following drug
release. Unfoldable systems are made of
biodegradable polymer; the concept is to make a
carrier, such as a capsule, incorporating a
compressed system, which extends in the
stomach. Proposed different geometric forms
(tetrahedron, ring or planar membrane (4-lobed,
disc or 4-limbed cross form) of biodegradable
polymer compressed within a capsule.
Swellable System
Swellable systems are also retained because of
their mechanical properties. The swelling
usually results from osmotic absorption of
water. The dosage form is small enough to be
swallowed, and swells in gastric liquids, the
bulk enable gastric retention and maintains
the stomach in a ‘fed’ state, suppressing
housekeeper waves.
Superporous Hydrogels
Although these are swellable systems, they
differ sufficiently from the conventional types to
warrant separate classification (Chen and park,
2000) with pore size ranging between 10 nm
and 10 µm. Absorption of water by
conventional hydrogel is very slow process and
several hours may be needed to reach an
equilibrium state during which premature
evacuation of the dosage form may occur.
Superporous hydrogel, average pore size > 100
µm, swell to equilibrium size within a minute,
due to rapid water uptake by capillary wetting
through numerous interconnected open pores.
Moreover they swell to a large size (swelling
ratio 100 or more) and are intended to have
sufficient mechanical strength to withstand
pressure by gastric contractions. This is
achieved by a co- formulation of a hydrophilic
particulate material, Ac-DiSol (cross carmellose
sodium).
Magnetic System
These systems appear as small gastroretentive
capsules containing a magnetic material, whose
elimination from the stomach is prevented by
the interaction with a sufficiently strong magnet
applied to the body surface in the region of the
stomach. Despite numerous reports about
successful tests, the real applicability of such
systems is doubtful because the desired results
can be achieved only provided that the magnet
position is selected with very high precision.
Probably, the development of new conveniently
applied magnetic field sources will improve this
concept.
Self-Unfolding Systems
The self-unfolding systems are capable of
mechanically increasing in size relative to the
initial dimensions. This increase prevents the
system from passing via the pylorus and
provides for its prolonged stay in the stomach.
A drug can be either contained in a polymeric
composition of the gastroretentive system or
included as a separate component. Several
methods were suggested to provide for the self-
unfolding effect.
The use of hydrogels swelling in contact
with the gastric juice.
Osmotic systems, comprising an osmotic
medium in a semi-permeable membrane.
Systems based on low-boiling liquids
converting into a gas at the body
temperature.
Formulation Aspects
The design of novel controlled release dosage
forms should take into account three important,
criteria, viz., drug, delivery, and destination.
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Excipients Used In FDDS
Following types of ingredients can be
incorporated into HBS dosage form in addition
to the drugs.
Figure12: Types of Gastroretentive Drug
Delivery Systems
Hydrocolloids
(20%-75%).They can be synthetics, anionic or
non-ionic like hydrophilic gums, modified
cellulose derivatives. Eg. Acacia, pectin,
Chitosan, agar, casein, bentonite, veegum,
HPMC (K4M, K100M and K15M), Gellangum
(Gelrite®),
Inert Fatty Materials
(5%-75%) Edible, inert fatty materials having a
specific gravity of less than one can be used to
decrease the hydrophilic property of formulation
and hence increase buoyancy. Eg. Beeswax,
fatty acids, and long chain fatty alcohols.
Effervescent Agents
Sodium bicarbonate, citric acid, tartaric acid,
DiSGC (Di-Sodium Glycine Carbonate), CG
(Citroglycine).
Disintegrating Agents
Povidone, Polyplasdone XL and XL-10
Viscolyzing Agents
Sodium alginate, Carbopol 934
Release Rate Accelerants
(5%-60%). eg lactose, mannitol
Release Rate Retardants
(5%-60%): Dicalcium phosphate, talc,
magnesium stearate
Buoyancy Increasing Agents
(upto80%): eg. EthylCellulose
Low Density Material
Polypropylene foam powder (Accurel MP
1000®).
Evaluation of Floating Drug Delivery
Systems
Pre-compression Parameters
a) Angle of Repose
The frictional forces in a loose powder or
granules can be measured by angle of repose.
This is the maximum angle possible between the
surface of a pile of powder or granules and the
horizontal plane. The granules were allowed to
flow through the funnel fixed to a stand at
definite height (h). The angle of repose was then
calculated by measuring the height and radius of
the heap of granules formed.
tan ϴ = h/r
ϴ = tan-1 (h/r)
Where, ϴ= angle of repose, h = height of the
heap, r = radius of the heap
Table 3: Relationship between Angle of Repose
and Powder Flow
Angle of repose Powder flow
< 25 Excellnt
25-30 Good
30-40 Passable
> 40 Very poor
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b) Compressibility Index
The flowability of powder can be evaluated by
comparing the bulk density (ρo) and tapped
density (ρt) of powder and the rate at which it
packed down. Compressibility index was
calculated by:
Compressibility index (%) = ρt – ρ0/ρt*100
Where ρ0= Bulk density g/cc, ρt= Tapped
density g/cc
Post-compression Parameters
a) Shape of Tablets
Compressed tablets were examined under the
magnifying lens for the shape of the tablet.
b) Tablet Dimensions
Thickness and diameter were measured using a
calibrated Vernier caliper. Three tablets of each
formulation were picked randomly and
thickness was measured individually.
c) Hardness
Hardness indicates the ability of a tablet to
withstand mechanical shocks while handling.
The hardness of the tablets was determined
using Monsanto hardness tester.
It was expressed in kg/cm2. Three tablets were
randomly picked and hardness of the tablets was
determined.
d) Friability test
The friability of tablets was determined by using
Roche Friabilator. It was expressed in
percentage (%). Ten tablets were initially
weighed (Winitial) and transferred into friabilator.
The friabilator was operated at 25rpm for 4
minutes or run up to 100 revolutions. The
tablets were weighed again (Wfinal). The %
friability was then calculated by
%F = 100 (1-W0/W)
% Friability of tablets less than 1% was
considered acceptable.
e) Tablet Density
Tablet density was an important parameter for
floating tablets. The tablet would floats only
when its density was less than that of gastric
fluid (1.004). The density was determined using
following relationship.
V = Πr2h
d = m/v, v = volume of tablet (cc), r = radius
of tablet (cm)
h = crown thickness of tablet (g/cc), m = mass
of tablet
f) Specific Gravity
Specific Gravity of the floating system can be
determined by the displacement method using
benzene as a displacing medium
g) Weight Variation Test
Ten tablets were selected randomly from each
batch and weighed individually to check for
weight initial variation. A little variation was
allowed in the weight of a tablet by U.S.
Pharmacopoeia. The following percentage
deviation in weight variation was allowed show
in table 4.
Table 4: Percentage Deviation in Weight
Variation
Average weight of a
tablet
Percent
deviation
130mg or less 10
>130mg and <324mg 7.5
324 mg or more 5
h) Buoyancy / Floating Test
The time between introduction of dosage form
and its buoyancy on the simulated gastric fluid
and the time during which the dosage form
remain buoyant were measured. The time taken
for dosage form to emerge on surface of
medium called Floating Lag Time (FLT) or
Buoyancy Lag Time (BLT) and total duration of
time by which dosage form remain buoyant is
called Total Floating Time (TFT).
i) Swelling Study
The swelling behavior of a dosage form was
measured by studying its weight gain or water
uptake. The dimensional changes could be
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measured in terms of the increase in tablet
diameter and/or thickness over time. Water
uptake was measured in terms of percent weight
gain, as given by the equation.
WU = W1 –W0/W0 x 100
Where, Wt = Weight of dosage form at
time t.
Wo = Initial weight of dosage form.
j) In-vitro Dissolution Study
Dissolution tests are performed using USP
dissolution apparatus. Samples are withdrawn
periodically from the dissolution medium;
replenished with the same volume of fresh
medium at sampling time points. Recent
methodology as described in the USP XXIII
states “the dosage unit is allowed to sink to the
bottom of the vessel before rotation of the blade
is started. A small, loose piece of non-reactive
material such as not more than a few turns of a
wire helix may be attached to the dosage units
that would otherwise float”. However, standard
dissolution methods based on the USP or British
Pharmacopoeia (BP) have been shown to be
poor predictors of in-vitro performance for
floating dosage forms12.
k) Drug Release
Dissolution tests are performed using the
dissolution apparatus. Samples are withdrawn
periodically from the dissolution medium with
replacement and then analyzed for their drug
content after an appropriate dilution.
l) X-Ray/Gamma Scintigraphy
X-Ray/Gamma Scintigraphy is a very popular
evaluation parameter for floating dosage form
now a day. It helps to locate dosage form in the
GIT and by which one can predict and correlate
the gastric emptying time and the passage of
dosage form in the GIT. Here the inclusion of a
radio-opaque material into a solid dosage form
enables it to be visualized by X-rays. Similarly,
the inclusion of a γ-emitting radionuclide in a
formulation allows indirect external observation
using a γ-camera or scintiscanner. In case of γ-
scintigraphy, the γ-rays emitted by the
radionuclide are focused on a camera, which
helps to monitor the location of the dosage form
in the GI tract13.
m) Pharmacokinetic Studies
Pharmacokinetic studies are the integral part of
the in vivo studies and several works has been
on that. Sawicki studied the pharmacokinetics of
verapamil, from the floating pellets containing
drug, filled into a capsule, and compared with
the conventional verapamil tablets of similar
dose (40mg). The tmax and AUC (0-infinity)
values (3.75 h and 364.65 ng.ml-1h
respectively) for floating pellets were
comparatively higher than those obtained for the
conventional verapamil tablets. (tmax value
1.21 h, and AUC value 224.22 ng.ml1h).No
much difference was found between the Cmax
values of both the formulations, suggesting the
improved bioavailability of the floating pellets
compared to the conventional tablets. An
improvement in bioavailability has also been
observed with piroxicam in hollow
polycarbonate microspheres administered in
rabbits14. The microspheres showed about 1.4
times more bioavailability, and the elimination
half-life was increased by about three times than
the free drug.
n) Drug-Excipient (DE) Interactions
This is done using FTIR. Appearance of a new
peak, and/or disappearance of original drug or
excipient peak indicate the DE interaction.
Apart from the above mentioned evaluation
parameters, granules (ex: Gelucire 43/01) are
also evaluated for the effect of ageing with the
help of Differential Scanning Calorimeter or
Hot stage polarizing microscopy.
Application of Floating Drug Delivery
System
Floating drug delivery offers several
applications for drugs having poor
bioavailability because of the narrow absorption
window in the upper part of the gastrointestinal
tract. It retains the dosage form at the site of
absorption and thus enhances the bioavailability.
These are summarized as follow:
Sustained Drug Delivery: Eg. Sustained release
floating capsules of nicardipine
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Site-Specific Drug Delivery: Eg. Furosemide
monolithic floating dosage.
Absorption Enhancement: Eg. A significantly
increase in the bioavailability of floating dosage
forms(42.9%) could be achieved as compared
with commercially available LASIX tablets
(33.4%) and enteric coated LASIX-long product
(29.5%).
Table 5: Marketed Products of Floating Drug
Delivery Systems
CONCLUSION
Gastroretentive drug delivery systems have
emerged as a current approaches of enhancing
bioavailability and controlled delivery of
drugs that exhibit an absorption window.
Gastroretentive drug delivery approaches
comprised mainly of floating, bioadhesive,
swelling, magnetic, and high density systems.
These systems not only provide controlled
release of the drug but also present the drug in
an absorbable form at the regions of optimal
absorption. All these drug delivery systems
have their own advantages and drawbacks. To
design a successful GRDDS, it is necessary to
take into consideration the physicochemical
properties of the drug, physiological events in
the GIT, formulation strategies, and correct
combination of drug and excipients.
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